Tin polyoxaalkanecarboxylates and compositions containing them

ABSTRACT

Tin polyaalkanecarboxylates having the formula [(R 1   p R 2   q Sn) r O s ] t  wherein R 1  represents C 1 -C 6  alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms, R 2  is carboxylic residue selected from (I), (II), (III) or (IV); and p, q, r, s and t have the following meanings: P=3, q=1, r=1, s=) and t=1, p=2, q=2, r=1, s=0, and t=1, p=2, q=1, r=2, s=1 and t=2, have anti-tumor activity.

REFERENCE TO RELATED APPLICATION

The present application is the Continuation of prior international application PCT/NL98/00429, filed Jul. 29, 1998, which designated the United States, and which international application was published under PCT Article 21 (2)in the English language. The entire contents of said PCT/NL98/00429 are hereby incorporated by reference.

The invention relates to novel tin polyoxaalkanecarboxylates and to anti-tumour compositions containing such compounds.

The anti-tumour activity of tin compounds is known; it is also known that the anti-tumour activity of tin compounds could be enhanced by increasing their solubility in water.

The invention now provides water-soluble tin compounds which show strong in vitro anti-tumour activities against a broad spectrum of tumours, as appears from the experimental part, disclosed hereinafter.

More specifically the invention relates to tin polyoxaalkanecarboxylates having the formula

[(R ¹ _(p) R ² _(q) Sn) _(r) O _(s)]_(t)

wherein

R¹ represents C₁-C₆ alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms,

R² is a carboxylic residue selected from:

and p, q, r, s and t have the following meanings:

p=3, q=1, r=1, s=0 and t=1;

p=2, q=2, r=1, s=0 and t=1;

p=2, q=1, r=2, s=1 and t=2.

According to a preferred embodiment of the invention, represents R¹ a phenyl group or a n-butyl group in a compound having formula (1), (2) or (3).

The compounds according to the invention can be synthesized by effecting a condensation reaction between a carboxylic acid having formula

with triaryltin hydroxide, trialkyltin acetate or dialkyltin oxide, preferably triphenyltin hydroxide, tri-n-butyltin acetate or di-n-butyltin oxide, according to the following reaction schemes:

a) RCOOH+(C₆H₅)₃SnOH→(C₆H₅)₃SnOCOR+H₂O

b) RCOOH+Bu₃SnOCOCH₃→Bu₂SnOCOR+CH₃COOH

c) 2RCOOH+Bu₂SnO→Bu₂Sn(OCOR)₂+H₂O

d) 2RCOOH+2Bu₂SnO→½{[Bu₂(RCOO)Sn]₂O}₂+H₂O

Different media and methods can be used to synthesize such derivatives

1) the condensation can be performed in toluene/ethanol. The water formed during the condensation is eliminated by azeotropic distillation (Dean-Stark funnel)

2) benzene can be used instead of toluene/ethanol

3) these compounds can also be prepared by a two-step procedure, dibutyltin oxide being first condensed with n-propanol to yield tetrabutyldipropoxydistannoxane:

2Bu₂SnO+2PrOH→(PrOSnBu₂)₂O+H₂O

In a second step, the carboxylic acid is added at room temperature to this tetrabutyldipropoxydistannoxane in the desired molar ratio.

The compounds synthesized by one of these methods were characterized by elemental analysis, ¹H, ¹³C and ¹¹⁷Sn NMR, electrospray mass spectrometry and ^(119m)Sn Mössbauer spectroscopy. Chromatography on Sephadex LH-20 proved to be a very efficient method to separate 3 (or 7) from 4 (or 8), or 11, 12, 15 and 16 from the starting carboxylic acid.

The structures of the compounds synthesized are depicted below

GENERALITIES AND ABBREVIATIONS

NMR spectra: CDCl₃ solutions; ¹H and ¹³C chemical shifts δ in ppm vs. TMS, homonuclear coupling constants in Hz, in parentheses; Mössbauer parameters (quadrupole splitting QS, isomers shift IS, and band widths Γ₁ and Γ₂) in mm/s; s: singlet; d: doublet; dd: doublet of doublets; m: complex pattern; t: triplet; tq: triplet of quartets; ψs, pseudo-singlet.

Electrospray mass spectra: positive monoisotopic ions (¹²C, ¹H, ¹⁶O, ²³Na, ³⁹K, ¹²⁰Sn). Na and/or K are already present in the electrospray mass spectra of the starting carboxylic acids.

Charaterization of Compounds 1 to 15

Compound 1: triphenyltin 4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3 (20),21-triene-1-carboxylate prepared according to method 1,

10 h of reflux, recrystallized from diethyl ether/hexane, m.p. 110-112° C., yield 98%, elemental analysis: exp. (calc. for C₃₅H₃₈SnO₈): C: 60.2 (59.60); H: 5.5 (5.43); ¹H NMR: 7.7-7.8, m, H(o) & H(5); 7.62, d (⁴J(¹H−¹H)=2), H(3); 7.4-7.5, m, H(m) & H(p); 6.91, d (³J(¹H−¹H)=9), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(11), H(14) & H(15); 3.67, ψs, H(12) & H(13); ¹³C NMR: 172.7, C(7); 152.9, C(1); 148.0, C(2); 138.5, C(i); 137.0, C(o) ²J(^(117/119)Sn−¹³C)=47/49; 130.2, C(p) ⁴J(^(117/119)Sn—¹³C)=13; 129.0, C(m) ³J(^(117/119)Sn−¹³C)=61/63; 125.1, C(5); 122.8, C(4); 114.9, C(3); 111.7, C(6); 70.80 & 70.77, C(10) & C(15); 70.71 & 70.66, C(12) & C(13); 70.53, 70.51, 69.4, 69.2, 68.8 & 68.6, C(8), C(9), C(11), C(14), C(16) & C(17); ¹¹⁷Sn NMR: −115.7; electrospray MS: M+K⁺(m/z=745), 14%; M+Na⁺, 100%; Mössbauer: QS: 2.26; IS: 0.55; Γ₁: 1.34; Γ₂: 1.32.

Compound 2: tri-n-butyltin 4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-carboxylate prepared according to method 1,

4 h of reflux, recryst. hexane/chloroform, m.p. 45-47° C., yield 80%, elemental analysis: exp. (calc. for C₂₉H₅₀SnO₈.H₂O): C: 52.5 (52.50); H: 8.3 (7.90); ¹H NMR: 7.63, dd (³J(¹H−¹H)=8; ⁴J(¹H−¹H)=2), H(5); 7.54, d (⁴J(¹H−¹H)=2), H(3); 6.82, d (³J(¹H−¹H)=8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(11), H(14) & H(15); 3.65, ψs, H(12) & H(13);˜2, HOH; 1.6-1.7, m H(β); 1.2-1.3, m, H(α) & H(γ); 0.89, t (³J(¹H−¹H)=7), H(δ); ¹³C NMR: 171.4, C(7); 152.2, C(1); 148.1, C(2); 125.0, C(4); 124.2, C(5); 115.0, C(3); 112.1, C(6); 70.96 & 70.84, C(10) & C(15); 70.77 & 70.73, C(12) & C(13); 70.66, 70.61, 69.5, 69.4, 68.9 & 68.8, C(8), C(9), C(11), C(14), C(16) & C(17); 27.9, C(β) ²J(^(117/119)Sn−¹³C)=20; 27.0, C(γ) ³J(^(117/119)Sn−¹³C)=62/65; 16.6, C(α) ¹J(^(117/119)Sn−¹³C)=341/358; 13.7, C(δ); ¹¹⁷Sn NMR: 108.2; electrospray MS: M+Na⁺ (m/z=669), 6%; M+H₂O+H⁺, 9%; M+H⁺, 11%; Mössbauer: QS: 3.40; IS: 1.39; Γ₁: 0.72; Γ₂: 0.85.

Compound 3: di-n-butyltin bis[4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-carboxylate, prepared according to method 1,

6 h of reflux, recryst. hexane/chloroform, m.p. 125-127° C., yield 96%, elemental analysis: exp. (calc. for C₄₂H₆₄SnO₁₆): C: 53.5 (53.46); H: 7.1 (6.84); ¹H NMR: 7.73, d (³J(¹H−¹H)=8) , H(5); 7.58, s, H(3); 6.86, d (³J(¹H−¹H)=8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(11), H(14) & H(15); 3.65, ψs, H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.37, tq, (³J(¹H−¹H)=7, ³J(¹H−¹H)=7), H(γ); 0.86, t (³J(¹-¹H)=7), H(δ); ¹³C NMR: 175.7, C(7); 153.3, C(1); 148.3, C(2); 124.9, C(5); 122.7, C(4); 115.3, C(3); 112.3, C(6); 70.9, C(10) & C(15); 70.81 & 70.76, C(12) & C(13); 70.73 & 70.67, 69.5, 69.4, 69.2 & 69.0, C(8), C(9), C(11), C(14), C(16) & C(17); 26.7, C(β) ²J(^(117/119)Sn−¹³C)=33; 26.3, C(γ) ³J(^(117/119)Sn−¹³C)=95; 25.4, C(α) ¹J(^(117/119)Sn−¹³C)=569/596; 13.5, C(δ); ¹¹⁷Sn NMR: −156.2; electrospray MS: M+Na⁺ (m/z 967), 100%; Mössbauer: QS: 3.41; IS: 1.44; ψ₁: 10.94; ψ₂: 0.94.

Compound 4: bis{di-n-butyl-[4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-carboxylato]tin}oxide, prepared according to method 3

12 h of reflux, Sephadex LH-20, elution with chloroform/methylene chloride; recryst. hexane/chloroform, m.p. 96-98° C., yield 90%, elemental analysis: exp. (calc. for C₁₀₀H₁₆₄Sn₄O₃₄): C: 50.0 (50.35); H: 7.1 (6.94); ¹H NMR: 7.54, d (³J(¹H−¹H)=8), H(5); 7.49, s, H(3); 6.84, d (³J(¹−¹H)=8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6 3.8, m, H(10), H(11), H(14) & H(15); 3.62, ψs, H(12) & H(13); 1.6-1.8, m, H(β); 1.4-1.6, m, H(α); 1.1-1.4, m, H(γ); 0.7-0.9, m, H(δ); ¹³C NMR: 172.6, C(7); 152.5, C(1); 148.3, C(2); 126.3, C(4); 124.0, C(5); 115.3, C(3); 112.4, C(6); 70.8, C(10) & C(15); 70.7 & 70.6, C(12) & C(13); 70.6, 70.5, 69.42, 69.35, 69.1 & 68.9, C(8), C(9), C(11), C(14), C(16) & C(17); 26.7 & 26.6, C(β); 27.6 & 27.4, C(γ); 29.5 & 28.3, C(α); 13.5 & 13.4, C(δ); ¹¹⁷Sn NMR: −213.0 & −217.3; electrospray MS: M/2+K⁺ (m/z=1233), 11%:; Mössbauer: QS: 3.36; IS: 1.27; Γ₁: 0.96; Γ₂: 0.99.

Compound 5: triphenyltin 4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3 (17),18-triene-1-carboxylate, prepared according to method 2,

48 h of reflux, recryst. hexane, m.p.: 130-131° C., yield 95%, elemental analysis: exp. (calc. for C₃₃H₃₄SnO₇.1 H₂O): C: 58.4 (58.34); H: 5.7 (5.35); ¹H NMR: 7.7-7.8, m, H(o) & H(5); 7.60, d (⁴J(¹H−¹H)=2), H(3); 7.4-7.5, m, H(m) & H(p); 6.82, d (³J(¹H−¹H)=8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-3.9, m, H(9) & H(14); 3.73, ψs, H(10), H(11), H(12) & H(13);˜2, HOH; ¹³C NMR: 172.8, C(7); 153.1, C(1); 148.3, C(2); 138.7, C(i); 136.9, C(o) ²J(^(117/119)Sn−¹³C)=47/49; 130.1, C(p) ⁴J(^(117/119)Sn—³¹C)=13; 128.9, C(m) ³J(^(117/119)Sn−¹³C)=62/65; 125.2, C(5); 123.3, C(4); 115.7, C(3); 112.1, C(6); 70.95 & 70.92, C(8) & C(15); 70.31 & 70.23, C(9) & C(14); 69.3, 69.2, 69.9 & 68.5, C(10), C(11), C(12) & C(13); ¹¹⁷Sn NMR: −116.3; electrospray MS: M+K⁺ (m/z=701, 67%); M+Na⁺, 73%; Mössbauer: QS: 2.77; IS: 1.23; Γ₁: 0.94; Γ₂: 0.88.

Compound 6: tri-n-butyltin 4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3 (17),18-triene-1-carboxylate, prepared according to method 2,

25 h of reflux, Sephadex LH-20, elution with chloroform/methylene chloride, liquid; yield 90%; elemental analysis: exp. (calc. for C₂₇H₄₆SnO₇.½ H₂O): C: 53.1 (53.14); H: 7.8 (7.77); ¹H NMR: 7.63, dd (³J(¹H−¹H)=8; ⁴J(¹H−¹H)=2), H(5); 7.54, d (⁴J(¹H−¹H)=2), H(3); 6.82, d (³J(¹H−¹H)=8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-3.9, m, H(9) & H(14); 3.73, ψs, H(10), H(11), H(12) & H(13); 1.6-1.7, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.89, t (³J(¹H−¹H)=7), H(δ); ¹³C NMR: 171.4, C(7); 152.5, C(1); 148.4, C(2); 125.1, C(4); 124.4, C(5); 115.5, C(3); 112.3, C(6); 71.2, C(8) & C(15); 70.57 & 70.52, C(9) & C(14); 69.6, 69.5, 69.1 & 68.9, C(10), C(11), C(12) & C(13); 27.9, C(β) ²J(^(117/119)Sn−¹³C)=20; 27.0, C(γ) ³J(^(117/119)Sn−¹³C)=62/65; 16.6, C(α) ¹J(^(117/119)Sn−¹³C)=350/362; 13.6, C(δ); ¹¹⁷Sn NMR: 107.4; electrospray MS: M+Na^(+(m/z=)625), 5%; M+NH₄ ⁺, 9%; Mössbauer: QS: 3.29; IS: 1.45; Γ₁: 0.94; Γ₂: 0.88.

Compound 7: di-n-butyltin bis[4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3(17),18-triene-1-carboxylate], prepared according to methode 2,

48 h of reflux, recrystallized from petroleum ether/methylene chloride, m.p.: 130-132° C.; yield 98%; elemental analysis: exp. (calc. for C₃₈H₅₆SnO₁₄): C: 53.9 (53.35); H: 6.7 (6.60); ¹H NMR: 7.74, dd (³J(¹H−¹H)=8, ⁴J(¹H−¹H)=2), H(5); 7.59, d (⁴J(¹H −¹H)=2) , H(3); 6.86, d (³J(¹H−¹H)=8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-4.0, m, H(9) & H(14); 3.75, ψs, H(10), H(11), H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.38, tq (³J(¹H−¹H)=7, ³J(¹H−¹H)=7), H(γ); 0.86, t (³J(¹H−¹H)=7), H(δ); ¹³C NMR: 175.8, C(7); 153.5, C(1); 148.5, C(2); 125.0, C(5); 122.9, C(4); 115.4, C(3); 112.2, C(6); 71.11 & 71.09, C(8) & C(15); 70.39 & 70.31, C(9) & C(14); 69.4, 69.2, 69.0 & 68.6, C(10), C(11), C(12) & C(13); 26.7, C(β), ²J(117/119Sn−¹³C)=34; 26.4, C(γ), ³J(^(117/119)Sn−¹³C)=103; 25.5, C(α), ¹J(^(117/119)Sn—³¹C)=561/588; 13.6, C(δ); ¹¹⁷Sn NMR: −156.8; electrospray MS: M+Na⁺ (m/z=879), 27%, M+K⁺, 27%; Mössbauer: QS: 3.28; IS: 1.41; Γ₁: 0.92; Γ₂: 0.93.

Compound 8: triphenyltin 3,6-diheptanoate, prepared according to method 2,

8 h of reflux, recrystallized from hexane/chloroform, m.p.: 100-102° C., yield 95%, elemental analysis: exp. (calc. for C₂₃H₂₄SnO₄): C: 57.4 (57.18); H: 4.7 (5.01); ¹H NMR: 7.7-7.8, m. H(o); 7.4-7.5, m, H(m) & H(p); 4.25, s, H(2); 3.7-3.8, m, H(4); 3.5-3.6, m, H(5); 3.35, s, H(7); ¹³C NMR: 176.5, C(1); 137.7, C(i); 136.8, C(o) ²J(^(117/119)Sn−¹³C)=49; 130.2, C(p) ⁴J(^(117/119)Sn−¹³C)=13; 128.9, C(m) ³J(^(117/119)Sn−¹³C)=62/65; 72.0, C(5); 70.6, C(4); 69.0, C(2); 59.0, C(7); ¹¹⁷Sn NMR: −100.0; electrospray MS: M+Na⁺ (m/z=507), 5%, M+H⁺, 2%; Mössbauer: QS: 3.60; IS: 1.24; Γ₁: 0.85; Γ₂: 0.79.

Compound 9: tri-n-butyltin 3,6-diheptanoate, prepared according to methode 2,

8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 95% elemental analysis: exp. (calc. for C₁₇H₃₆SnO₄.½ H2O): C: 47.4 (47.27); H: 8.6 (8.63);; ¹H NMR: 4.09, S, H(2); 3.6-3.7, m, H(4); 3.5-3.6, m, H(5); 3.36, S, H(7);˜2, HOH; 1.5-1.6, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.88, t (³J(¹H−¹H)=7), H(δ); ¹³C NMR: 175.2, C(1); 71.9, C(1); 70.4, C(4); 69.0, C(2); 59.0, C(7); 27.8, C(β) ²J(^(117/119)Sn−¹³C)=20; 27.1, C(γ) ³J(^(117/119)Sn−¹³C)=64/67; 16.6, C(α) ¹J(^(117/119)Sn−¹³C)=338/355; 13.7, C(8); ¹¹⁷Sn NMR: 120.7; electrospray MS: M+Na⁺ (m/z=447), 7%; Mössbauer: QS: 3.81; IS: 1.47; Γ₁: 1.15; Γ₂: 1.14.

Compound 10: di-n-butyltin bis(3,6-diheptanoate), prepared according to method 3,

12 h of reflux, liquid, yield 98%; elemental analysis: exp. (calc. for C₁₈H₃₆SnO₈): C: 43.4 (43.31); H: 7.5 (7.27); ¹H NMR: 4.16, s, H(2); 3.6-3.8, m, H(4); 3.5-3.6, m, H(5); 3.36, s, H(7); 1.6-1.7, m, H(β) & H(α); 1.34, tq (³J(¹H−¹H)=7, ³J(¹H−¹H)=7), H(γ); 0.87, t (³J(¹H−¹H)=7), H(δ); ¹³C NMR: 178.3, C(1); 71.8, C(5); 70.7, C(4); 68.6, C(2); 59.0, C(7); 26.5, C(β) ²J(^(117/119)Sn−¹³C)=34; 26.3, C(γ) ³J(^(117/119)Sn−¹³C)=98/102; 25.7, C(α) ¹J(^(117/119)Sn−¹³C)=538/567; 13.4, C(δ); ¹¹⁷Sn NMR: −124.7; electrospray MS: M+Na⁺ (m/z=523), 77%; M+K⁺, 13%; Mössbauer: QS: 3.90; IS: 1.44; Γ₁: 1.28; Γ₂: 1.02.

Compound 11: bis[di-n-butyl(3,6-dioxaheptanoato)tin]oxide, prepared according to method 3,

12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 80%; elemental analysis: exp. (calc. for C₅₂H₁₀₈Sn₄O₁₈.2H₂O): C: 40.7 (40.76); H: 7.2 (7.37); ¹H NMR: 3.95, s, H(2); 3.6-3.7, m, H(4); 3.5-3.6, m, H(5); 3.34, s, H(7);˜2, HOH; 1.5-1.7, m, H(β); 1.3-1.5, m, H(α); 1.30, tq, (³J(¹H−¹H)=7, ³J(¹H−¹H)=7), H(γ); 0.86, m, H(δ); ¹³C NMR: 174.9, C(1); 71.8, C(5); 70.2, C(4); 69.8, C(2); 58.9, C(7); 27.5 & 27.2, C(β); 26.8 & 26.7, C(γ); 29.0 & 26.3, C(α); 13.57 & 13.55, C(δ); ¹¹⁷Sn NMR: −204.8 & −215.8; electrospray MS: M/2+Bu₂SnOH⁺(m/z=1001), 40%; Mössbauer: QS: 3.42; IS: 1.34; Γ₁: 1.22; Γ₂: 1.18.

Compound 12: triphenyltin 3,6,9-trioxadecanoate, prepared according to method 2,

8 h of reflux, recryst. diethyl ether/methylene chloride, m.p.: 109-111° C., yield 92%, elemental analysis: exp. (calc. for C₂₅H₂₈SnO₅): C: 57.1 (56.96); H: 5.4 (5.36);; ¹H NMR: 7.7-7.8, m, H(o); 7.4-7.5, m, H(m) & H(p); 4.22, s, H(2); 3.7-3.8, m, H(4); 3.6-3.7, m, H(5); 3.5-3.6, m, H(7); 3.4-3.5, m, H(8); 3.34, s, H(10); ¹³C NMR: 176.4, C(1); 137.8 C(i); 136.9, C(o) ²J(^(117/119)Sn−¹³C)=47-50; 130.2, C(p) ⁴J(^(117/119)Sn−¹³C)=13; 128.9, C(m) ³J(^(117/119)Sn−¹³C)=63/66; 72.0, C(8); 70.7, 70.7 & 70.5, C(4), C(5) & C(7); 69.0, C(2); 59.0 C(10);¹¹⁷Sn NMR: −103.2; electrospray MS: M+K⁺(m/z=567), 2%; M+Na⁺, 11%; M+H⁺, 6%; Mössbauer: QS: 3.44; IS: 1.29; Γ₁: 0.91; Γ₂: 0.87.

Compound 13: tri-n-butyltin 3,6,9-trioxadecanoate, prepared according to method 2,

8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 92%;elemental analysis: exp. (calc. for C₁₉H₄₀SnO₅.½H₂O): C: 47.7 (47.94); H: 8.8 (8.68); ¹H NMR: 4.09, s, H(2); 3.6-3.8, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.36, s, H(10);˜2, HOH, 1.5-1.7, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.89, t (³J(¹H−¹H)=7), H(δ); ¹³C NMR: 175.1, C(1); 72.0, C(8); 70.6, 70.5 & 70.5, C(4), C(5) & C(7); 69.0, C(2); 58.9, C(10); 27.8, C(β) ²J(^(117/119)Sn−¹³C)=20; 27.0, C(γ) ³J(^(117/119)Sn−¹³C)=63/66; 16.6, C(α) ¹J(^(117/119)Sn−¹³C)=349/355; 13.6, C(δ); ¹¹⁷Sn NMR: 120.7; electrospray MS: M+K⁺(m/z=507), 18%; M+Na⁺, 51%; Mössbauer: QS: 3.84; IS: 1.47; γ₁: 1.07; Γ₂: 1.02.

Compound 14: di-n-butyltin bis (3,6,9-trioxadecanoate), prepared according to method 3,

12 h of reflux, liquid, yield 95%; elemental analysis: exp. (calc. for C₂₂H₄₄SnO₁₀): C: 44.8 (44.99); H: 7.8 (7.56); ¹H NMR: 4.15, s, H(2); 3.6-3.8, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.35, s, H(10); 0.6-0.8, m, H(β) & H(α); 1.35, tq (³J(¹H−¹H)=7, ³J(¹H−¹H)=7), H(γ); 0.88, t (³J(¹H−¹H)=7), H(δ); ¹³C NMR: 175.8, C(1); 71.8, C(8); 71.1, 70.6 & 70.4, C(4), C(5) & C(7); 68.7, C(2); 59.0, C(10); 26.6, C(β), ²J(^(117/119)Sn−¹³C)=38; 26.3, C(γ), ³J(^(117/119)Sn−¹³C)=99; 25.6, C(α), ¹J(^(117/119)Sn−¹³C)=540/567; 13.5, C(δ); ¹¹⁷Sn NMR: −124.1; electrospray

MS: M+K⁺(m/z=627), 12%; M+Na⁺, 22%; Mössbauer: QS: 3.77; IS: 1.42; Γ₁: 1.36; Γ₂: 1.18.

Compound 15: bis[di-n-butyl(3,6,9-trioxadecanoato)tin]oxide, prepared according to method 3,

12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, elemental analysis: exp. (calc. for C₆₀H₁₂₄Sn4O₂₂.2 H₂O): C: 42.2 (42.18); H: 7.4 (7.56); yield 80%; ¹H NMR: 3.96, s, H(2); 3.6-3.7, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.34, s, H(10);˜2, HOH; 1.57, tt (³J(¹H−¹H)=7, ³J(¹H−¹H)=7), H(β); 1.4-1.5, m, H(α); 1.27, tq (³J(¹H−¹H)=7, ³J(¹H−¹H)=7), H(γ); 0.8-0.9, m, H(δ); ¹³C NMR: 175.1, C(1); 72.0, C(8); 70.60, 70.55 & 70.4, C(4), C(5) & C(7); 69.9, C(2); 59.0, C(10); 27.6 & 27.3, C(β); 26.9 & 26.7, C(γ); 29.1 & 25.8, C(α); 13.6, C(δ); ¹¹⁷Sn NMR: −204.9 & −217.6; electrospray MS: M/2+Na⁺ (m/z=861), 10%; M/2+Bu₂SnOH⁺, 33%; Mössbauer: QS: 3.49; IS: 1.32; Γ₁: 0.90; Γ₂: 0.90.

Stability in Water of Organotin Polyoxaalkanenecarboxylates

The stability in the presence of water of four compounds, 6, 8, 9 and 12, was determined. Solutions in CD₃CD₂OD exhibit a single resonance in ¹¹⁷Sn NMR (at 36.5, −210.7, 27.9 and −212.0 ppm, respectively) that is regularly slightly shifted after the addition of increasing amounts of D₂O.

Antitumour activity of compounds 1 to 15

The ID₅₀ inhibition doses in ng/ml of the tested compounds are given in the table as well as those for some known reference compounds.

IG- MCF-7 EVSA-T WiDr ROV M19 A498 H226 1 15 12 13 30 16 43 37 2 35 6 11 30 70 97 100 3 155 128 781 260 219 282 281 4 36 46 239 82 68 126 73 5 <3 <3 <3 <3 <3 <3 <3 6 <3 <3 <3 <3 <3 <3 <3 7 273 237 332 321 286 49 854 8 13 12 34 37 31 32 33 9 32 40 82 84 90 153 61 10 60 62 379 128 115 134 161 11 <3 <3 6 <3 <3 <3 5 12 9 9 19 33 24 21 25 13 36 25 40 89 78 93 56 14 86 66 495 178 167 145 280 15 <3 <3 3 <3 <3 <3 <3 cisplatin 699 422 967 169 558 2253 3269 doxorubicin 10 8 11 60 16 90 199 etoposide 2594 317 150 580 505 1314 3934 5-fluoro-uracil 750 475 225 297 442 143 340 methotrexate 18 5 <3 7 23 37 2287

Inhibition doses ID₅₀ in vitro (in ng/ml) against some tumoural cell lines of human origin, two mammary cancers, (MCF-7, EVSA-T), a colon carcinoma (WiDr), an ovarian cancer (IGROV), a melanoma (M19 MEL), a renal cancer (A 498) and a non small cell lung cancer (H226) of organotin derivatives of carboxybenzocrown and di- or trioxaalkanecarboxylic acids, and of some known reference compounds. 

What is claimed is:
 1. Tin polyoxaalkanecarboxylates having the formula [(R¹ _(p)R² _(q)Sn)_(r)O_(s)]_(t) wherein R¹ represents C₁-C₆ alkyl, branched or straight, or a phenyl group R² is a carboxylic residue selected from

and p, q, r, s and t have the following meanings: p=3, q=1, r=1, s'0 and t=1; p=2, q=2, r=1, s'0 and t=1; or p=2, q=1, r=2, s'1 and t=2.
 2. An anti-tumour composition, containing as an active ingredient one or more tin polyoxaalkanecarboxylates of claim 1 of the formula R¹ ₃SnR²  (1); R¹ ₂SnR² ₂  (2); or {[R¹ ₂R²Sn]₂O}₂  (3), and, when only one said active ingredient is present, a pharmaceutically acceptable carrier.
 3. A composition according to claim 2, containing a compound having the formula (1), (2) or (3) as defined in the claim 1, wherein R¹ represents a phenylgroup or a n-butylgroup.
 4. A compound according to claim 1 of the formula R¹ ₃SnR²  (1); R¹ ₂SnR² ₂  (2); or {[R¹ ₂R²Sn]₂O}₂  (3). 